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View the Table of Contents for the July 15 issue of Cancer Research.
Gomez et al. Page 6908
POT1 (protection of telomere 1) is a specific single-stranded telomere-binding protein involved in telomere capping and T-loop maintenance and is thought to regulate G-quadruplex conformation at the telomere. To explore its role in the mechanism of action of telomestatin, a potent G-quadruplex-interacting ligand with antitumoral properties, Gomez et al. examined binding of POT1 to a reconstituted telomeric overhang and the localization of GFP-POT1 to telomeric foci in human cells. The approach indicated that POT1 is rapidly and selectively removed from telomeres and confirms that telomestatin induces major modifications of the telomeric end structure, leading to the dysfunction of this essential telomere component.
Riggins et al. Page 7007
Resistance to antiestrogens is a significant clinical problem in treating estrogen receptor–positive breast tumors. Riggins et al. investigated the mechanisms by which high expression of the scaffolding molecule Cas (also called BCAR1) confers resistance to tamoxifen. They found that Cas mediates tamoxifen resistance through its ability to bind to, and activate, the protein tyrosine kinase c-Src. Two substrates of c-Src, STAT5b and tyrosine 845 on the EGFR, were also found to be important for resistance. The identification of this Cas/c-Src/EGFR/STAT5 pathway as a mediator of tamoxifen resistance provides new avenues for therapeutic intervention geared toward reversing the resistance phenotype.
Page 7016
Mesenchymal progenitor cells (MPCs) are believed to constitute a common origin of at least a subset of sarcomas. Riggi et al. have recently observed that bone marrow-derived MPCs expressing the EWS-FLI-1 fusion protein form Ewing’s sarcoma-like tumors. Because MPCs colonize several tissues, including adipose tissue, they may also provide an origin of myxoid liposarcoma. In the present study, the authors show that MPC expressing the FUS-CHOP fusion protein form tumors with transcriptional and phenotypic features associated with human myxoid liposarcoma. These observations suggest that MPCs may constitute a candidate cell of origin of two distinct sarcomas and that, like EWS-FLI-1 in Ewing’s sarcoma, FUS-CHOP expression may initiate the pathogenesis of myxoid liposarcoma.
Page 7095
Several groups have used transcriptional profiling of “training sets” of tumors to develop signatures predictive of outcome. Fournier et al. describe a novel unsupervised strategy to identify predictive signatures for breast cancer using 3D culture models of differentiating nonmalignant human mammary epithelial cells (HMECs). These cells proliferate for several days before forming growth-arrested, polarized mammary acini. A panel of genes was identified which distinguishes proliferative from quiescent HMECs in 3D culture, and breast tumors expressing the highest levels of this gene signature had the poorest outcome. This study underscores the value and potential clinical relevance of 3D culture models.